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Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing

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Abstract

Retinitis pigmentosa (RP) is the most common and highly heterogeneous form of hereditary retinal degeneration. This study was to identify mutations in the 60 genes that were known to be associated with RP in 157 unrelated Chinese families with RP. Genomic DNA from probands was initially analyzed by whole exome sequencing. Sanger sequencing was used to confirm potential candidate variants affecting the encoded residues in the 60 genes, including heterozygous variants from genes that are related to autosomal dominant RP, homozygous or compound heterozygous variants from genes that are related to autosomal recessive RP, and hemizygous variants from genes that are related to X-linked RP. Synonymous and intronic variants were also examined to confirm whether they could affect splicing. A total of 244 candidate variants were detected by exome sequencing. Sanger sequencing confirmed 240 variants out of the 244 candidates. Informatics and segregation analyses suggested 110 potential pathogenic mutations in 28 out of the 60 genes involving 79 of the 157 (50 %) families, including 31 (39 %, 31/79) families with heterozygous mutations in autosomal dominant genes, 37 (47 %, 37/79) families with homozygous (9) or compound heterozygous (28) mutations in autosomal recessive genes, and 11 (14 %, 11/79) families with hemizygous mutations in X-linked genes. Of the 110 identified variants, 74 (67 %) were novel. The genetic defects in approximately half of the 157 studies families were detected by exome sequencing. A comprehensive analysis of the 60 known genes not only expanded the mutation spectrum and frequency of the 60 genes in Chinese patients with RP, but also provided an overview of the molecular etiology of RP in Chinese patients. The analysis of the known genes also supplied the foundation and clues for discovering novel causative RP genes.

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Acknowledgments

The authors are thankful to all of the patients and controls for their participation in this study. This study was supported by the National Natural Science Foundation of China (U1201221) and the Fundamental Research Funds of State Key Laboratory of Ophthalmology. The funders had no participation in the study design or in the data collection and analysis. The funders also did not take part in the decision to publish or in the preparation of the manuscript.

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Authors and Affiliations

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou, 510060, China

    Yan Xu, Tao Shen, Xueshan Xiao, Shiqiang Li, Xiaoyun Jia, Xiangming Guo & Qingjiong Zhang

  2. BGI-Shenzhen, Shenzhen, 518083, China

    Liping Guan, Jianguo Zhang, Hui Jiang, Jianhua Yang, Ye Yin & Jun Wang

Authors
  1. Yan Xu
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  2. Liping Guan
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  3. Tao Shen
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  4. Jianguo Zhang
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  5. Xueshan Xiao
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  6. Hui Jiang
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  7. Shiqiang Li
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  8. Jianhua Yang
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  9. Xiaoyun Jia
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  10. Ye Yin
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  11. Xiangming Guo
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  12. Jun Wang
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  13. Qingjiong Zhang
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Corresponding author

Correspondence to Qingjiong Zhang.

Additional information

Y. Xu and L. Guan contributed equally. J. Wang and Q. Zhang contributed equally.

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Xu, Y., Guan, L., Shen, T. et al. Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing. Hum Genet 133, 1255–1271 (2014). https://doi.org/10.1007/s00439-014-1460-2

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  • DOI: https://doi.org/10.1007/s00439-014-1460-2

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